Document Detail

Cbl-b is a critical regulator of macrophage activation associated with obesity-induced insulin resistance in mice.
MedLine Citation:
PMID:  23349502     Owner:  NLM     Status:  MEDLINE    
We previously reported the potential involvement of casitas B-cell lymphoma-b (Cbl-b) in aging-related murine insulin resistance. Because obesity also induces macrophage recruitment into adipose tissue, we elucidated here the role of Cbl-b in obesity-related insulin resistance. Cbl-b(+/+) and Cbl-b(-/-) mice were fed a high-fat diet (HFD) and then examined for obesity-related changes in insulin signaling. The HFD caused recruitment of macrophages into adipose tissue and increased inflammatory reaction in Cbl-b(-/-) compared with Cbl-b(+/+) mice. Peritoneal macrophages from Cbl-b(-/-) mice and Cbl-b-overexpressing RAW264.7 macrophages were used to examine the direct effect of saturated fatty acids (FAs) on macrophage activation. In macrophages, Cbl-b suppressed saturated FA-induced Toll-like receptor 4 (TLR4) signaling by ubiquitination and degradation of TLR4. The physiological role of Cbl-b in vivo was also examined by bone marrow transplantation and Eritoran, a TLR4 antagonist. Hematopoietic cell-specific depletion of the Cbl-b gene induced disturbed responses on insulin and glucose tolerance tests. Blockade of TLR4 signaling by Eritoran reduced fasting blood glucose and serum interleukin-6 levels in obese Cbl-b(-/-) mice. These results suggest that Cbl-b deficiency could exaggerate HFD-induced insulin resistance through saturated FA-mediated macrophage activation. Therefore, inhibition of TLR4 signaling is an attractive therapeutic strategy for treatment of obesity-related insulin resistance.
Tomoki Abe; Katsuya Hirasaka; Sachiko Kagawa; Shohei Kohno; Arisa Ochi; Kenro Utsunomiya; Atsuko Sakai; Ayako Ohno; Shigetada Teshima-Kondo; Yuushi Okumura; Motoko Oarada; Yoichi Maekawa; Junji Terao; Edward M Mills; Takeshi Nikawa
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-01-24
Journal Detail:
Title:  Diabetes     Volume:  62     ISSN:  1939-327X     ISO Abbreviation:  Diabetes     Publication Date:  2013 Jun 
Date Detail:
Created Date:  2013-05-24     Completed Date:  2013-08-02     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  0372763     Medline TA:  Diabetes     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1957-69     Citation Subset:  AIM; IM    
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MeSH Terms
Adaptor Proteins, Signal Transducing / genetics,  metabolism*
Cell Line
Flow Cytometry
Insulin Resistance / genetics,  physiology
Macrophage Activation / genetics,  physiology
Mice, Knockout
NF-kappa B / metabolism
Obesity / genetics,  metabolism*,  physiopathology*
Proto-Oncogene Proteins c-cbl / genetics,  metabolism*
Real-Time Polymerase Chain Reaction
Grant Support
Reg. No./Substance:
0/Adaptor Proteins, Signal Transducing; 0/NF-kappa B; EC 6.3.2.-/Proto-Oncogene Proteins c-cbl; EC protein, mouse

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